The present invention relates to compounds of Formula (I) depicted hereinbelow, which compounds are xcex23 adrenergic receptor agonists and, accordingly, have utility as, inter alia, hypoglycemic, and anti-obesity agents.
The invention further relates to intermediates useful in the preparation of the compounds of Formula (I); to combinations of the compounds of Formula (I) with anti-obesity agents; to pharmaceutical compositions comprising such compounds and combinations; and to methods of using the compounds, combinations, and pharmaceutical compositions in the treatment of xcex23 adrenergic receptor-mediated diseases, conditions, or disorders in a mammal. The compounds and combinations of the invention also possess utility for increasing the content of lean meat in edible animals, i.e. ungulate animals such as cattle, swine, and the like, as well as poultry.
The compounds and combinations of this invention further possess utility in the treatment of intestinal motility disorders, depression, prostate disease, dyslipidemia, and airway inflammatory disorders.
The disease diabetes mellitus is characterized by metabolic defects in the production and utilization of carbohydrates which result in the failure to maintain appropriate blood sugar levels. The results of these defects include, inter alia, elevated blood glucose or hyperglycemia. Research in the treatment of diabetes has centered on attempts to normalize fasting and postprandial blood glucose levels. Current treatments include administration of exogenous insulin, oral administration of drugs and dietary therapies.
Two major forms of diabetes mellitus are recognized. Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), is the result of an absolute deficiency of insulin, the hormone that regulates carbohydrate utilization. Type 2 diabetes, or non-insulin-dependent diabetes mellitus (NIDDM), often occurs with normal, or even elevated, levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin. Most Type 2 diabetic patients are also obese.
The compounds of the invention effectively lower blood glucose levels when administered orally to mammals with hyperglycemia or diabetes.
Obesity constitutes a major health risk that leads to mortality and incidence of Type 2 diabetes mellitus, hypertension, and dyslipidemia. In the United States, more than 50% of the adult population is overweight, and almost 25% of the population is considered to be obese. The incidence of obesity is increasing in the United States at a three-percent cumulative annual growth rate. While the vast majority of obesity occurs in the United States and Europe, the prevalence of obesity is also increasing in Japan. Furthermore, obesity is a devastating disease which can also wreak havoc on an individual""s mental health and self-esteem, which can ultimately affect a person""s ability to interact socially with others. Unfortunately, the precise etiology of obesity is complex and poorly understood, and societal stereotypes and presumptions regarding obesity only tend to exacerbate the psychological effects of the disease. Because of the impact of obesity on society in general, much effort has been expended in efforts to treat obesity, however, success in the long-term treatment and/or prevention thereof remains elusive.
The compounds, pharmaceutical compositions, and combinations of the invention also reduce body weight or decrease weight gain when administered to a mammal. The ability of the compounds to affect weight gain is due to activation of xcex23 adrenergic receptors which stimulate the metabolism of adipose tissue.
xcex2-Adrenergic agents have been generally classified into xcex21, xcex22, and xcex23 receptor-specific subtypes. Agonists of xcex2-receptors promote the activation of adenyl cyclase. Activation of xcex21 receptors invokes an increase in heart rate while activation of xcex22 receptors induces smooth muscle tissue relaxation which produces a drop in blood pressure and the onset of skeletal muscle tremors. Activation of xcex23 receptors is known to stimulate lipolysis (e.g., the breakdown of adipose tissue triglycerides into glycerol and fatty acids) and metabolic rate (energy expenditure), thereby promoting the loss of fat mass. Accordingly, compounds that stimulate xcex23 receptors are therefore useful as anti-obesity agents, and can be further used to increase the content of lean meat in edible animals. In addition, compounds that are xcex23 receptor agonists have hypoglycemic activity, however, the precise mechanism of this effect is presently unknown.
Until recently, xcex23 adrenergic receptors were thought to be found predominantly in adipose tissue, however, xcex23 receptors are now known to be located in such diverse tissues as the intestine, (J. Clin. Invest., 91, 344 (1993)) and the brain Eur. J. (Pharm., 219, 193 (1992)). Stimulation of xcex23 receptors has also been demonstrated to induce relaxation of smooth muscle in the colon, trachea, and bronchi. See, for example, Life Sciences, 44, 1411 (1989), Br. J. Pharm., 112, 55 (1994), and Br. J. Pharmacol., 110, 1311 (1993). Furthermore, stimulation of xcex23 receptors has also been found to induce relaxation of histamine-contracted guinea pig ileum. See, for example, J. Pharm. Exp. Ther., 260, 1, 192 (1992).
The xcex23 receptor is also expressed in the human prostate (J. Clin. Invest., 91, 344 (1993). Because stimulation of the xcex23 receptor causes relaxation of smooth muscles that have been shown to express the xcex23 receptor, i.e. intestinal smooth muscle, one of ordinary skill in the art would also predict relaxation of prostate smooth muscle. Therefore, xcex23 agonists are useful in the treatment or prevention of prostate disease.
Commonly assigned U.S. Pat. No. 5,977,124 discloses certain xcex23 adrenergic receptor agonists having utility in the treatment of, inter alia, hypoglycemia and obesity.
U.S. Pat. No. 5,776,983 discloses certain catecholamines useful as xcex23-agonists.
U.S. Pat. No. 5,030,640 discloses certain xcex1-heterocyclic ethanol amino alkyl indoles, which are useful as growth promoters, bronchodilators, anti-depressants, and anti-obesity agents.
U.S. Pat. No. 5,019,578 discloses certain xcex1-heterocyclic ethanolamines useful as growth promoters.
U.S. Pat. No. 4,478,849 discloses pharmaceutical compositions comprising certain ethanolamine derivatives and methods of using such compositions in the treatment of obesity and/or hyperglycaemia.
U.S. Pat. No. 4,358,455 discloses certain heterocyclic compounds of the structural formula Hetxe2x80x94CHOHxe2x80x94CH2xe2x80x94NHxe2x80x94aralkyl, which compounds are useful for treating glaucoma and cardiovascular disease.
European Patent Application Publication No. 0 516 349, published Dec. 2, 1992, discloses certain 2-hydroxyphenethyl amines which possess anti-obesity, hypoglycemic, and related utilities.
U.S. Pat. No. 5,153,210 discloses certain heterocyclic compounds of the formula Roxe2x80x94Xxe2x80x94CH(OH)xe2x80x94CH2xe2x80x94N(R1)xe2x80x94C(R2)(R3)xe2x80x94(CH2)nxe2x80x94Yxe2x80x94Axe2x80x94R4xe2x80x94R5 which compounds are useful as anti-obesity and anti-hyperglycaemic agents.
PCT International Patent Application Publication No. WO 99/65877, published Dec. 23, 1999, discloses heterocyclic compounds having the structural formula 
which compounds are useful for the treatment of diseases susceptible to amelioration by administration of an atypical beta-adrenoceptor agonist.
The instant invention provides xcex23 adrenergic receptor agonists of structural Formula (I), 
the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, wherein Ar, R, R1, R2, R3, R4, R5, R6, R7, R8, X, and Y are as defined hereinbelow.
In another aspect, the invention provides intermediates useful in the preparation of the compounds of Formula (I); to combinations of the compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, with anti-obesity agents; to pharmaceutical compositions comprising the compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, or pharmaceutical compositions comprising the compounds of Formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, and anti-obesity agents; and methods of treating xcex23 adrenergic receptor-mediated diseases, conditions, or disorders in a mammal which methods comprise administering to the mammal an effective amount of a compound of Formula (I), a stereoisomer or prodrug thereof, or a pharmaceutical composition thereof; or a combination of a compound of Formula (I), a pharmaceutically acceptable salt of the compound, stereoisomer, or prodrug, and an anti-obesity agent, or a pharmaceutical composition thereof, acceptable salt of the compound, stereoisomer, or prodrug, and an anti-obesity agent, or a pharmaceutical composition thereof.